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Relationship between thyrotropin receptor hinge region proteolytic posttranslational modification and receptor

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Area of Science:

  • Endocrinology and Molecular Biology
  • Protein Structure and Function
  • Receptor Biology

Background:

  • The glycoprotein hormone receptor hinge region is highly variable.
  • The TSH receptor (TSHR) hinge is the longest and undergoes in vivo cleavage.
  • Previous studies could not define the minimal functional hinge region.

Purpose of the Study:

  • To determine the maximum deletions in the TSHR hinge region compatible with normal function.
  • To investigate the role of hinge region residues in TSHR signaling.

Main Methods:

  • Progressive deletion mutagenesis of the TSHR hinge region.
  • Functional assays measuring TSH binding and cAMP signal transduction.
  • Analysis of TSHR cleavage and subunit association.

Main Results:

  • Deletion of TSHR hinge residues 317-366 is tolerated.
  • The downstream limit for hinge deletion is residue 371.
  • Deletions of residues 303-366 (64 aa) or 307-371 (65 aa) maintain TSHR function.
  • Hinge residues 377-384 are important for coupling ligand binding to signal transduction.

Conclusions:

  • TSHR hinge deletions up to 65 amino acids are compatible with normal receptor function.
  • Specific downstream hinge residues are crucial for TSHR signaling.
  • This study defines the maximal functional hinge region deletions for TSHR.